The present invention relates to new 6-amino- or 6-hydrazino-sulphonyl-3-quinolylphosphonic acid compounds and to compositions containing them.
The prior art describes compounds that are capable of countering the excitatory and toxic effects of the excitatory amino acids (EAA) by blocking the initial activation of the AMPA (xcex1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptor (EP 0 640 612). Their usefulness is accordingly recognised for inhibiting pathological phenomena, especially neurotoxic phenomena associated with hyperactivation of the neurotransmission paths to the excitatory amino acids. Those compounds pose serious problems of nephrotoxicity, however, as has also been shown to be the case for other non-NMDA (N-methyl-D-aspartate) antagonists of reference, such as, for example, 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) (Journal of Cerebral Blood Flow and Metabolism, 1994, 14, 251-261).
The Applicant has discovered new compounds that have more powerful non-NMDA antagonist properties than do the compounds of the prior art, with greatly reduced associated nephrotoxicity. Those compounds are therefore new and are potential powerful therapeutic agents for the acute, and also chronic, treatment of neurological and psychological disorders involving those amino acids, for example degenerative disorders such as cerebrovascular accident, cerebral or spinal traumatism, epilepsy, chronic neurodegenerative diseases such as Alzheimer""s disease, schizophrenia, lateral amyotrophic sclerosis or Huntington""s chorea.
More especially, the present invention relates to compounds of formula (I): 
wherein:
R1 represents a halogen atom or a trifluoromethyl group,
R2 represents a hydrogen atom or an alkyl or cycloalkyl group,
R3 represents an alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, hydroxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl, arylcarbonyl or arylalkylcarbonyl group or an NHR6 group (wherein R6 represents a hydrogen atom or an alkyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, arylalkyl or arylalkylcarbonyl group),
or R2 and R3 together form with the nitrogen atom carrying them a ring having 5 or 6 carbon atoms, in which one of the carbon atoms can be replaced by an oxygen, nitrogen or sulphur atom or by an SO or SO2 group or by an NRa group (wherein Ra represents a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group),
R4 and R5, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group or a group 
xe2x80x83(wherein R7 and R8, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group),
it being understood that:
xe2x80x9calkylxe2x80x9d is understood to mean a linear or branched alkyl group containing from 1 to 6 carbon atoms,
xe2x80x9calkoxyxe2x80x9d is understood to mean a linear or branched alkoxy group containing from 1 to 6 carbon atoms,
xe2x80x9ccycloalkylxe2x80x9d is understood to mean a cyclic alkyl group containing from 3 to 8 carbon atoms,
xe2x80x9carylxe2x80x9d is understood to mean the groups phenyl or naphthyl, it being possible for those groups to be unsubstituted or substituted by from 1 to 3 groups selected from alkyl, cycloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, polyhaloalkyl, SO2NR9R10 (wherein R9 and R10, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group) and halogen atoms,
their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of nonand-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are compounds of formula (I) wherein R1 represents a chlorine atom.
The preferred groups R3 are the alkyl group (such as, for example, methyl or propyl), the dialkylaminoalkyl group (such as, for example, dimethylaminoethyl), the aryl group (such as, for example, phenyl), the arylcarbonyl group (such as, for example, benzoyl) or the group NHCOR wherein R represents an alkyl or aryl group.
An advantageous aspect of the invention relates to compounds of formula (I) wherein R2 is a hydrogen atom, or an alkyl group.
When R2 is a hydrogen atom, R3 advantageously represents the groups cycloalkyl, aryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, hydroxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl or NHR6.
When R2 is an alkyl group, R3 advantageously represents the group alkyl.
The hydrogen atom is the preferred meaning for the substituents R4 and R5.
More especially still, the invention relates to compounds of formula (I) which are:
7-chloro-2-oxo-6-[(n-propylamino)sulphonyl]-1,2-dihydro-3-quinolylphosphonic acid,
7-chloro-6-[(methylamino)sulphonyl]-2-oxo-1,2-dihydro-3-quinolylphosphonic acid,
6-(anilinosulphonyl)-7-chloro-2-oxo-1,2-dihydro-3-quinolylphosphonic acid,
6-[(2-benzoylhydrazino)sulphonyl]-7-chloro-2-oxo-1,2-dihydro-3-quinolylphosphonic acid,
7-chloro-6-[(2-{4-[(di-n-propylamino)sulphonyl]benzoyl}hydrazino)sulphonyl]-2-oxo-1,2-dihydro-3-quinolylphosphonic acid, and
7-chloro-6-({[2-(dimethylamino)ethyl]amino}sulphonyl)-2-oxo-1,2-dihydro-3-quinolylphosphonic acid hydrobromide.
The enantiomers, diastereoisomers and pharmaceutically acceptable addition salts with an acid or a base of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein R1 is as defined for formula (I),
which is condensed, in the presence of a base, such as, for example, pyridine, with a compound of formula (III): 
to yield a compound of formula (IV): 
wherein R1 is as defined hereinbefore,
which is cyclised in the presence of a catalytic amount of piperidine to obtain a compound of formula (V): 
wherein R1 is as defined hereinbefore,
which is subjected to a mixture of nitric acid and sulphuric acid to yield a compound of formula (VI): 
wherein R1 is as defined hereinbefore,
which is reduced using palladium-on-carbon in the presence of hydrogen or iron in a dilute alcoholic medium to yield a compound of formula (VII): 
wherein R1 is as defined hereinbefore,
which is subjected, after conversion to the corresponding diazonium salt, to the action of sulphur dioxide in the presence of CuCl2 to yield a compound of formula (VIII): 
wherein R1 is as defined hereinbefore,
which is condensed with a compound of formula HNR2R3 wherein R2 and R3 are as defined for formula (I) to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1, R2 and R3 are as defined hereinbefore,
which is partially or totally deprotected in the presence of, for example, trimethylsilane bromide to yield a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein R1, R2 and R3 are as defined hereinbefore and R1 represents a hydrogen atom or an ethyl group,
which may be condensed with a compound of formula (IX): 
wherein Rxe2x80x3 represents an alkyl, aryl or arylalkyl group or a group 
(wherein R7 and R8 are as defined for formula (I)),
to obtain a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein R1, R2, R3, R5 and Rxe2x80x3 are as defined hereinbefore,
which compounds of formulae (I/a) to (I/c) constitute the totality of the compounds of formula (I), and can be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of the invention have very valuable pharmacological properties since they are powerful inhibitors of the AMPA receptor, and they are moreover selective since they do not affect the NMDA receptor and therefore do not have any of the side-effects described for NMDA antagonists, and especially do not have the nephrotoxicity associated with a number of AMPA/non-NMDA antagonists. The use of those compounds as inhibitors of pathological phenomena associated with hyperactivation of the neurotransmission paths to the excitatory amino acids will therefore be particularly appreciated in the acute, and especially chronic, treatment of neurological and psychological disorders involving those amino acids, for example degenerative disorders such as cerebrovascular accident, cerebral or spinal traumatism, epilepsy, chronic neurodegenerative diseases such as Alzheimer""s disease, schizophrenia, lateral amyotrophic sclerosis or Huntington""s chorea.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragxc3xa9es, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments and ranges from 50 mg to 1 g per 24 hours in 1 or more administrations.
The following Examples illustrate the invention and do not limit it in any way.